The primary goals of this program are to increase understanding of the structure and function of neurotransmitter systems in the overall operation of the mammalian central nervous system (CNS), and the molecular mechanism of action of drugs which act on the CNS, as well as the mechanism(s) through which the immune and other peripheral systems are influenced by the CNS in normal and disease states. The multidisciplinary approach utilized in this program employs rational drug design based on structure-activity relations and molecular modeling, modern organic chemical synthesis, pharmacology, biochemistry, immunology and requires collaboration with other appropriate disciplines. Elucidation of the molecular structure and mechanism of action of the ligand-receptor systems and their antagonists provides new opportunities for the design of superior drugs and insight into disorders which are now little-understood. Synthetic programs are continuing to develop new ligands for imaging brain drug receptors by positron emission tomography (PET) and single photon emission computed tomography (SPECT) scanning. Our data provide evidence for four kappa opioid receptor subtypes in guinea pig brain. Quantitative autoradiographic studies demonstrated that two of these kappa sites are heterogeneously distributed, and that their anatomical distribution is different than those previously reported. We have synthesized optically pure tritium labeled IS,2S-(-)-trans-2-isothiocyanato-N-methyl-N-[2- (1-pyrrolidinyl)cyclohexyl]benzeneacetamide, an affinity ligand specific for the kappa receptor. We have developed a monoclonal antibody to isolate and biochemically characterize brain opioid receptors. An opioid receptor from mouse brain was purified with a molecular weight of 65,000 -daltons. The opioid receptor isolated from brain tissue was found to be structurally and antigenically 11 similar to the delta-class opioid receptor from NG108-15 cells and cells of the immune system. The NIH Opiate Total Synthesis continues to be employed to provide previously inaccessible unnatural enantiomers of opiates and derivatives as new pharmacological agents and research tools.